Ketone body synthesis (ketogenesis) occurs exclusively in hepatic mitochondria. The rate-limiting regulated enzyme in ketogenesis that is NOT a simple condensation but an irreversible committed step is:

• A HMG-CoA lyase — cleaves HMG-CoA to acetoacetate + acetyl-CoA, the committed ketogenic step
• B Thiolase (acetyl-CoA acetyltransferase) — condenses 2 acetyl-CoA to acetoacetyl-CoA
• C HMG-CoA synthase (mitochondrial) — condenses acetoacetyl-CoA + acetyl-CoA to HMG-CoA ✓
• D beta-hydroxybutyrate dehydrogenase — reduces acetoacetate to beta-hydroxybutyrate

Explanation

The ketogenic pathway: acetyl-CoA → acetoacetyl-CoA (thiolase) → HMG-CoA (mitochondrial HMG-CoA synthase, mHMGCS) → acetoacetate + acetyl-CoA (HMG-CoA lyase) → beta-hydroxybutyrate. Mitochondrial HMG-CoA synthase (mHMGCS) is the rate-limiting and regulated step of ketogenesis. It is induced by fasting/glucagon (via FOXA2 transcription factor) and inhibited by succinylation and by its own product feedback. Thiolase is reversible and present in many pathways. HMG-CoA lyase is irreversible but not the regulated step. The cytosolic HMG-CoA synthase (cHMGCS) is the separate enzyme for cholesterol synthesis.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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